Prolonged-action preparations of d-tubocurarine salts and methods of preparing same



Patented July 12, 1949 PROLONGED-ACTION PREPARATIONS OF D-TUBOCURARINE SALTS AND METH- ODS OF PREPARING SAME John C. Burke, Milltown, N. J., and Alfred E. Jurist, Brooklyn, N. Y., assignors to E. R. Squibb & Sons, New York, N. Y., a corporation of New York No Drawing. Application October 1, 1946,

Serial No. 700,370

7 Claims. (Cl. 16767) This invention relates to preparations of drugs having a relaxing eifect on the voluntary musculature, especially to preparations of d-tubocurarine chloride (the highly active alkaloid isolated from curare).

Curare is a plant extract characterized by its relaxing effect on the voluntary musculature; and both the stable, physiologically-standardized preparations of curare (cf. U. S. Patent No. 2,397,417 dated March 26, 1946) and the d-tubocurarine chloride isolated from curare have been shown to have exceptional utility in the treat-' ment of spastic paralysis; in combination with anesthesia during surgical operations; as an adjunct to the shock therapy of certain mental conditions; and for other medical purposes.

In the treatment of spastic children, the curare preparation or d-tubocurarine chloride was injected intravenously to produce a relaxation of the voluntary musculature, reducing incoordination, athetosis, and dysarthria, and permitting physical therapy under favorable conditions (muscle training, under such relaxation, constituting a very important part of the treatment). This relaxation of the voluntary musculature, however, was transient; and although some prolongation of the relaxing eifect was obtained on intramuscular-injection of the drug (in aqueous solution), the danger of too rapid or variable absorption of the injected drug was introduced, and the prolongation obtained was not to the desired extent. Because of the low margin of safety of these drugs (the range of dosage between that giving the desired skeletal-muscle effect and that giving the undesirable toxic paralysis of the muscles of respiration), the prospects of obtaining a preparation capable of safely producing a prolonged relaxation of the voluntary musculature were not too bright.

It is the object of this invention to provide preparations capable of safely producing a prolonged relaxation of the voluntary musculature, and methods of obtaining such preparations.

It has been found that suspension of d-tubocurarine chloride, for example, in an oily medium suitable for intramuscular-injection and containing myricin, for example, results in a preparation capable (on intramuscular-injection) of safely producing a prolonged relaxation of the voluntary-musculature. It has been further found that subdivision of d-tubocurarine chloride sufiicient to give a uniform suspension canbe efficiently and satisfactorily accomplished by lyophilizing or freeze-drying an aqueous solution thereof (i. e., by freezin the solution and subjecting the solid to a high vacuum to sublime off the water).

While providing a satisfactory suspension, the lyophilized d-tubocurarine chloride has a tendency to settle out and agglutinate' on warming the suspension to ampule it or to transfer it to a syringe, and resuspension is difficult to eifect and introduces the dangerous possibility of irregular dosage. It has been found that this tendency to settle out or agglutinate may be substantially eliminated by including in the aqueous solution of d-tubocurarine'chloride to be lyophilized a water-soluble alkaline-earth-metal salt of a physiologically-acceptable organic acid, especially of a physiologically-acceptable hydroxy-aliphatic acid. The dry product thus obtained is in a fine state of subdivision; and when suspended, the particles thereof have little or no tendency to settle out or agglutinate. -Moreover the suspension obtained has such stability that it can" be heat-sterilized, as well as heated for the purposes of subdividing multiple-dose ferring to a syringe.

The preparations of this invention essentially comprise d-tubocurarine chloride or equivalent thereof (1. e;, a curarizlng drug, or drug having qualitatively the same relaxing effect on the voluntary musculature ascurare) in an oily medium suitable for intramuscular injection and containing myricin or equivalent thereof (i. e.', a physiologically-acceptable, wax-like substance, or an agent capable of delaying the absorption of watersoluble particles suspended in an oily medium). Thus, in place of (the preferred) d-tubocurarine chloride, one may. -employ other Water-soluble salts of the corresponding quaternary base dtubocurarine (inter' alia, d-tubocurarine sulfate and d-tubocurarine iodide), as well as derivatives of the quatern'ar'ybase having qualitatively the same relaxing effect. on the voluntary musculature, inter alia, d'-'chondocurine'dimethiodide, and d-tubocurarine 'dimethyle'ther iodide. Thus also, in place of (the preferred) myricin (the primary component of beeswax), one may'employ beeswax itself. other (true) waxes (natural or synthetic), other wax-like components of the'natural waxes, synthetic wax-like homologues of these wax-like components, and mixtures thereof (inter alia,

packages, and trans of physiologically-acceptable hy'droxy-aliphatic acids preferred for the purposes of this invention are the calcium salts of the sugar-derived acids, notably calcium. s-lactatefl-cThe proportion. of

d-tubocurainei chloride toecalciuni lactate, afor example, may vary within rather wide limits, say

.100:..Holaday units/mL, for example, being satisabout 1:.05 to about 1:4 (by weight); but a proportion of about 1:1 is preferred. The concen tration of the aqueous solutiontc. bedried may":

vary from about 0.6 to about 3.0.1g. 'of"d-'tubocu-- J rarine chloride per 100 ml., concentrations above" 1.5 g./100 ml. being obtained -1iyzincliiding=10% of ethanol in the aqueous solutiom The following examples are illustrativ of:-t'he invention Example 1 700 mg. of d-tubocurarine chloride (having a potency of 6.17 Holaday units/mg.) and a quana v Then,while. .the..suspensionisiwarm; it is. sub -v 5 divided into .measuredidoses. and vampuled, and

the ampuled preparation sterilizedby heating to 120. C.=f0 1:..three. hours; Theproduchthus obtained .is: an- (.ampuledlestable suspension capable on intramuscwaminjection'oilsafelykproducing a; 5

pr0l0nged=relaxatioir of ':the .-voluntary .vmuscula ture. I

. Example 2 ti1leal= .watei,'"and' 'the solutioni isa-freezemried. Following therprocedui e :des'cribedin Example 1 the dry productthus fobtained iweighing'ilfi mg.)

is suspended in aimixtureof 3 9:3ml: :peanut oil" 4 and rzozgsmyricim antl the suspension-is ampuled andesteril-ized.

Theacalciumtlactateziemployd' inreither' of 'the' foregoingx'exampleszmay bezreplaced byr-theisame amount of calcium gluconate (on 'ani'anhydrous basis)=' tofiobtain 2a" rpreparati'om havingt substan tiall'y th e same stability.v V

Aistable suspension wapabla 'o'nfiintramuscularsuch physiologically-acceptable substances as cetyl alcohol. The proportion of myricin, for example, in the oily medium may vary widely, proportions as low as about 3%, for example, being satisfactory for the purposes of this invention. Also, the proportion of the d-tubocurarine chloride (or preparation thereof) suspended in the oily-medium may .vary widelm-proportions as low as. about 2%; for example; or proportions yielding a preparation having a potency of about factory for the purposes of this invention.

Theinvention maybe variously otherwise embodied within;thei'scope of the appended claims.

"We claim: 1. A"preparatio'n capable on intramuscularcomprising asuspension of the solid obtained on gorlyophilizing an aqueous solution of a water-soluble salt of d-tubocurarine containing a water-soluble alkaline-earth-metal salt of a member of the groupconsisting of lactic acid and gluconic acid, in an oily medium suitable for intramuscularinjectiori and containing a physiologicall accept able'waxi-likesubstance, the 'preparati'dn:having a moisture content below ahout flfi t%.

2. l A" ::preparation capablei oni intramuscular 1 injection of safely producing a prolonged'relaxa tion ofvthe -ivoluntaryl" musculature; essentially comprising a suspensioncfcthe' solidrobtained: on: lyophil'izirrg :an=":'aque'ous'fisolution o'f d tuboeur-k arine"chloride containing a :water -solubletalka; 1 line earth metal salt. of .:a .member 'ofsthwgroup consisting of lactieilaciduand gluconicacidfinf an oily mediumsuitable-tfor intramuscular-injection and r'c'ontainin i imyri'cini the -preparationvhavingi;;

a moisture content belowv about10z07%:

3. Aiipre'pfil-aitiOndicaipablfii OIIZ ZIHtEamHSGIIIBLIF l q y 91111390 mg;l iga mmm mt t sm an 40 injection of-safely producingia'prolonged re'laxa anhydrousaibasismare elissol ved i 100 '-ml. dis-- tion"ofwtl're ivoluntary mu c fl e y 7 comprising axsuspenslon. ofsthe isolidn obtained-5' on lyophiiizin gian: aqueous solution 'Ofi d'3tuboi-.;-

' curarine chloride' containing ical'ciuma l'acta'teiin Ame'dium Es-uitable fonintramuscular irijecan oily tionr and'containingimyricinttheipreparation hairing a moisturel'content below about 0.07%;

4. A preparation sscap'able orr intramuscula'r injection ofisafely producing a prolonged relaxa tion" of" the: voluntary: musculature; essentially comprisingzsazsuspension' of lthESOlid-Dbtfliflfid on lyophilizing m aqueous'solution of'*d-"tubocura"- rine chloride monta-ining :calcium lactate; in ana injection of producing'a prolongedrelaxation o'f oily d m u ta l -"f nt am u ar ni tioh"* the voluntary musculature isialsmobtained when 5 andicoiitaining' myricin;stheiproportionof d tubo the 1.0 gurnyricin irrvExample: .2v issreplacd-by' curarine-cchlorideitoeicalcium. lactate rbein'g be tweemaboutrl .05 and-about 11:4 and-the preparer the peanut oil zanybatheisuspensioiisdescribeci' iv tion havinga moisture contentibelowab fl hereinbeforeiisreplaced' bysesamei oil; I

The presence or a: small'sam'ounte of fimoisture in aqueous: solution" of"-'d+tubocurarine chloride con the preparationsof thisinventiotr disproportion-- I '5. -The compositiorrtobtained by lyophilizing an.

ately increases athe'trate ofriabsurpti'on; thus, sthe presence of as'flittle 'as abnu' result in over 'curariz'ation Accordingly; mare should; be taken to. have thei' ingredients oi 'these preparations substantially :drmJ-and 'to'rsubstantially exclude moisture'riuning preparatiom .pack-- aging-.(ampuhngar;and:steamesterilizatiom (as by :07%-rmoisture may -r- 0f a-me'mber ofrthe roupiconsisting bf'lacticacid :.f

and gluconic acid. I

- 6.cThe-method onobtaining.a preparation capable onrintramuscular-injection oftisafiely provide" ing aiprolongedirelaxation of'dilieivoluntary mus-iculaturegicomprising lyopl'iilizing a-n aqueous s'olutiOILOfJEAWEtGI-SfihlblfiSalt of'sd'tubocurarine eontainingza:waterssolublemlkaline earthmetalEsaItof a rmemberiof fthlz'glbupstCOHSiSbing of l'actie acid-andugluconic zacid gairdisusperr'ding the=dryi productwthus obtained in-ia substantiallyr rdry oily T medium.suitableg'for intramuscularainjectiori' sand 1 1 containing;2aaphysiologicallyacceptablavwaxelike z;

muscuIar-injectiomsuch asrmi'xtures. of oilsrwithr w substance:

REFERENCES CITED The following referenlces are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date Re. 18,364 'I'ival Feb. 27, 1932 1,791,878 Strauck Feb. 10, 1931 2,055,083 Klein et a1 Sept. 22, 1936 2,149,304 Masucci Mar. 7, 1939 2,397,417 Holaday Mar. 26, 1946 OTHER REFERENCES Code et al., Proceedings of the Society for Experimental Niology and Medicine, June 1940, pages 475-477.

Code et al., American J. Physiology, June 1941,

16 pages 240-241. (Copies in Division 43.) 

